Establishing an accurate neuropathological diagnosis is a critical function of the Alzheimer's Disease Center (ADC) Neuropathology Cores and is a prerequisite to all tissue-based research. Although chronic traumatic encephalopathy (CTE), primary age-related tauopathy (PART), argyrophilic grain disease (AGD) and aging- related tau astrogliopathy (ARTAG) are all age-related tauopathies, each has distinctive patterns of abnormal tau deposition. Additionally, each has specific, but overlapping, effects on cognitive and neuropsychiatric function. Neuropathological criteria to diagnose CTE, PART, AGD and ARTAG have been recently proposed, yet no modules exist to capture these disorders in the National Alzheimer's Coordinating Center (NACC) database. Without rigorous, reproducible protocols for the diagnosis of age-related tauopathies, their disease- specific contributors to late life cognitive and neuropsychiatric impairment may be overlooked and obscured. This proposal will draw on the neuropathological expertise of Drs. Ann McKee, Dennis Dickson, and John Crary, who have pioneered investigations of CTE, AGD and PART. We will use 250 cases of AD and age- related tauopathies from the Boston University, Mayo Clinic Jacksonville and Mount Sinai ADCs to identiify novel tau and inflammatory markers that accurately detect and distinguish the age-related tauopathies. After re-examining tissue from the NACC-Neuropathology Data Set (NDS), we will establish the frequency of CTE, PART, AGD and ARTAG among individuals who had ante-mortem clinical diagnoses of normal cognition, mild cognitive impairment, or dementia. We will determine the unique contribution of these disorders to clinical diagnosis and to cognitive and neuropsychiatric impairment. We will also determine whether examining under- studied brain regions, namely the prefrontal cortex, uncal gyrus and amygdala identifies new cases of age- related tauopathies and whether pathology in these regions contributes to neuropsychiatric impairment. Lastly, we will apply knowledge gained from this project to develop CTE, PART, AGD and ARTAG assessment and diagnostic modules that we will use to organize an international NIH consensus conference to harmonize the neuropathological diagnoses of the age-related tauopathies for general use. Overall, this proposal will address critical, yet still unknown issues related to CTE, PART, AGD and ARTAG: 1) Identification of novel tau and neuroinflammatory biomarkers to aid in detection and discrimination of the age-related tauopathies, 2) Determination of age-related tauopathy frequency among memory disorder clinic patients; 3) Determination of age-related tauopathy contribution to cognitive and neuropsychiatric impairment; and 4) Development of harmonized criteria for age-related tauopathy neuropathological diagnosis. This project will also enrich the existing NACC-NDS, making data on age-related tauopathies available to other researchers. Overall, the successful completion of this proposal will transform the way we conceptualize the tauopathies and will facilitate future research on the diagnosis, treatment, and prevention of AD and related disorders.